N(alkyl,beta-4-morpholylalkyl) aminoalkanol esters



ber.

Patented June 20, 1944 N (ALKYL,fi-4-MORPHOLYLALKYL) I AMINOALKANOL ns'raas Elmore Hathaway Northey and Martin Everett Hultquist, Bound Brook, N. J., assignors to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application April 8, 1942,

' Serial No. 438,115

6 Claims. (01. 260-247) The present invenion relates to N(alkyl',fl-4- morpholylalkyl)aminoalkanol esters of carbocyclic substituted aliphatic carboxylic acids.

N-disubstituted aminoalcohols form alkamine esters of various carbocyclic substituted aliphatic carboxylic acids which are of considerable com-' mercial importance particularly with respect to the monobasic acids. The exact properties and consequently the uses to which they may be put depend upon the particular acid and particular aminoalcohol. which go to make up the ester. The

new compounds of the present invention, the es-' ters of the new N(alkyLB-4-m0rpholylalkyi)aminoalkanols and dicarbocyclic substituted aliphatic carboxylic acids are analogousto the morpholinoalkanol esters of our copending application Serial No. 438,114, filed April 8, 1942. Several of the compounds of the present invention show marked hypnotic and sedative properties and are characterized by an extremely low toxicity. Several of the compounds in addition are useful as modifiers in the vulcanization of natural and synthetic rub- The compounds of the present invention may be represented by the type formula I H: H:

Alki c-c 'l AC AlcN Alkz-N\ o 1 in which Ac is an acyl radical of a mono or polybasic acid, AM is an alcohol residue, Alki is an alkyl radical, Alkz is the residue of the same or a different alkyl radical and a: is a small whole number. Ac may be any dicarbocyclic=substituted monobasic or polybasic acyl radical such as diarylacetyl, alkoxydiarylacetyl, diarylpropionyl, dialicyclicacetyl, aryl-alicyclicacetyl, diarylsuccinyl and the like or may be hydroxy-substituted acyls such as benzilyl, tolilyl, anisilyl, naphthilyl and the like. a: i usually 1 or 2 although polybasic acyl groups having more than two (COQH) groups such as corresponds to citric acid are within the contemplation of the present invention.

These esters in general are oily liquids insoluble in water and soluble in alcohol, acetone and benzene. handled in the form of their salts which may be easily prepared since the esters themselves are .basic in reaction." The hydrochlorides, for example, are in general white crystalline salts, usually soluble in water. If so desired other salts such as the nitrate, sulfate, hydrobromide, tartrate,

They are usually more conveniently Quaternary derivatives such as the methiodide, ethobromide and the like may also be readily made by first treating the base in an alcohol solution with a compound such as methyl or ethyl bromide and precipitating the salt.

The invention will be more Iully set forth in connection with the following'examples which are illustrative only and not by way of limitation. All parts are by weight unless otherwise noted.

EXAMPLE 1 Preparation of N (ethyLB-4-morpholylethyl) aminoethanol N-fl-aminoethyl morpholine was reacted with -acetaldehyde and the reaction product reduced with metallic sodium in ethyl alcohol. The product, N-fl ethylaminoethyl morpholine, was then treated with ethylene oxide to produce the j 25 N(ethyLBA-morpholylethyl) amlnoethanol.

EXAMPLE 3 The procedure of stituting ethylene chlorohydrin for the ethylene The procedure of Example 1 was repeated substituting 1-3 propylenechlorohydrin for the ethylene oxide the product was -N(ethyl,p-4-morpholylethyl) aminopropanol.

In a similar manner any aminoalcohol falling within the general formula R-OH may be built up in which R represents thegroup in which the substituents have the same meaning given above. 'Alkz may be varied by starting citrate and the like may be readily prepared. with the appropriate N-aminoalkylmorpholine.

Example 1 was repeated, sub-- Alkrmay bevaried byusinz the proper-aldehyde. sene distilled of! under reduced pressure. The A10 may be varied by using the appropriate alkylester base remained as a viscous yellowish brown ene oxide or chlorohydrin. Where Alc is the resiliquid. 4

due or an n-alcohol, the proper alilorolliiydr'in 5 Exams: 7 I Md be Methyl, p-l-morpholulethfll).aminoethul 1 9 m a cum r u f d-di-p-tolylpropionate hydrochloride g I I CH .'mthur -r-mmahozvletnmsmmoetrw; diphen- I O H| H: CH o r I --0 can 0 0-0 1:01 0 \wcmml-cnn-o-tl- -rr 0-0. H: H: H.

a the treatment of Example 1. The product aped 1 l c tl m lti 194-196 solved in-150parts oibenzeneandbroughttoa ,pear c temperature of reflux. 63 parts of N(ethyl,p-4-

EXAIPI-I 8 morpholylethyl) aminoethanol were then s'radu- 2 m u p-4-morpholylethylmminomowl ally added and the mixture refluxed until the u 1 as partsoi diphenylacewl chloridewere disdiphenulacetate reaction was completed. The mixture was then cooled .to roonr temperature, the precipitated N(ethyl,p-4-morpholylethyl) -aminoethanol hydrochloride filtered out and the benzene evap- Ha H: c orated under reduced pressure. The residue oom- N 3 v a the ester base was left behind as 8 viscous 1 0 CsH4N-C Ia0H|0Hr- H lis t brown liquid. a

- Exams 5 N(ethul, p-l-momholulethybaminoethul diphenylacetate hydrochloride .1 64 parts oi the 'y-N(ethyl, p-4-morpholylethyl) 15 1g: 0 aminopropanol were slowly added to a refluxing \N solution or 86 parts of diphenylacetyi chloride I."' in imparts of benzene and the mixture refluxed 3-}; no] it until the reaction was completed and then cooled l I V J pholylethyl) aminopropanol hydrochloride/which The product of Example 4 was dissolved in 45 magnum was filtered out up! the benzen dryether and hydrogen chloride gas bubbled through until precipitation was complete. 'Crystals were collected and purified by recrystallization from an alcohol-acetone-ether solution. The

, product, a heavy Mscous liquid was -y-N(ethyl, p 4 morpholylethyl) aminopropyl diphenylaoepurified product appeared as colorless flufly crysm tals melting at lee-139 c. a 9 V y a-Methyl,--p-4-momholylethul)aminobutul Exmt: 8 uiphenulacetate N(eth1ll, p-l-morpholylethfllmminoethul w I a,a-di-p-tolylprgptonate am r 50 o N-0iHi1- I-cmcmcmcm-o-'a- -n c-c a m as 6 parts 1 of a- N(ethyl, p-l-morpholylethyl) amino-n butanol-wereslowly added to a refluxin; solution of 36 partsoi diphenylacetyl chloride The product of Example ":6 was subjected to to room temperature. The q-N(ethyl, p-4-morremoved under reduced pressure.- The residual 17 pa ts of a,a-di-p-tolylpropionyl chloride in 150 parts of benzene and the mixture refluxed were lved in parts of benzene to which untilthereaction was completed and then cooled were added 25 parts of N(ethyl, p-4-morpholyle to room temperature. The t-N(ethyl, s-i-morethynaminoethanol and the mixture refluxed pholylethyDaminobutanol hydrochloride which until'the-reaction flwas substantially completed. precipitated was filtered out and the'benzene Alter cooling to 20 '-c. the precipitated N(ethyl, -remove'd-u-n'der reduced pressure. The residual p-4 morpho1ylethy1) aminoethanol v hydrochloride product was a-N(eth'yl, ,s-i-morpholylethyl) amiwas removed by filtration-and the residualbennqbutyl diphenyla'cetflt- EXAMPLE N (ethyl, fl-4-1norplwlylethyl) aminoethyl dinaphthylacetate HI Hr c-c 0,11. o NCH:CH:-NCB:CHi-0ClH product, was N(ethyl, p-4-morpholylethyl)aminoethyl dinaphthylacetate.

EXAMPLE 11 N (ethyl, s-el-morpholylethyl) aminoethyl 5,5-diphenylpropionate parts of s,,a-diphenylpropionic acid were mixed with parts of thionyl chloride and refiuxed gently for of an hour after which the excess thionyl chloride was distilled oil. The acid the end of this period more parts of ethanol were chloride residue was takenup in 400 parts of anhydrous ether and 58 parts of N(ethyl, 3-4- morpholylethyl)aminoethanol added thereto,

and Holmes application Serial No. 431,822, filed February 21, 1942. .Preferably the alcohol which is replaced by the aminoalcohol is-continuously removed as it is formed. This procedure will be illustrated by the following samples.

parts of ethyl benzilate, 225' parts 0 N (ethyl,p-4-morpholylethyl) aminoethanol an 0.2 part of metallic sodium were placed in a flash attached to a total-reflux variable take-off fractionating column. The pressure was r'educed to Y 100 mm. and the heat was applied by an oil bath the temperature of which was slowly raised to 90 C. During three hours of heating 17 parts of ethanol distilled (355 0.). When the distillation of the ethanol became slow, the bath temperature was ralsed'to C. When the vapor temperature indicated distillation of the aminoalcohol the take-off valve was closed and the mixture was refluxed until the temperature ceased to drop. At

distilled. The remaining aminoalcohol was slowly distilled until its stopped. The pressure was then reduced to 20 mm; and the remainder of the aminoalcohol distilled at about 70 C. During the. reaction the color of the solution changed from yellow to deep red. The residue was dissolved in 500 parts of ether, washed once with dilute brine,

and three times with water, dried over sodium sulfate and finally dried over calcium sulfate. 500 parts of a saturated solutionjof-HCl in absolute ether was added and the resulting precipitate filtered. Dry HCl gas was passed into the filtrate I to a slight excess and the precipitate again filwhile the mixture was stirred and gently heated.

When all the components were added the mixture was refluxed until the reaction was completed and then cooled to 10 C., and filtered. A

The filtrate was extracted, several times with dilute hydrochloric acid, the extracts combined and the ester base precipitated therefrom with tered. The combined precipitates were'washed with cold acetone. The product was purified by recrystallization from acetone as fine white crysthe addition of sodium carbonate, as an oily liquid. The oily liquid' was taken up in ether,

dried over anhydrous sodium sulfate and finally the ether distilled 'oiT. The oily liquid residue was N(ethyl, p-e-morpholylethyl) aminoethyl p.5- diphenylpropionate.

While the preceding examples have been made by the reaction of an acid chloride and the morpholino alkanol, the invention is not so limited. For example, in the cases of compounds derived from hydroxy-acids such as benzilic acid, alkoxyacids suchas methoxydiphenylglycollic acid and dibasic acids such assymmetrical diphenylsuccinic acid, the acid chloride cannot be prepared at all or, only with great difficulty and in poor yield. Accordingly. the esters may be best formed by some type of alcoholysis. Anytype or alcohoiysis reaction may be used'but our preferred procedure is to first form a simple alkyl ester of the acid and then carry out a catalyzed ester interchange using metallic sodium or potassium as a catalyst according to the process of the Hill To a solution of 2 parts of sodium in 400 parts of N(ethyl,,s-4-morpholylethy1) aminoethanol was added 260 parts of diethyldiphenyls'ucclnate and the mixture heated at about C. until the reaction stopped, at the end of which period the.

excess N(ethyl,,B-4-morpholylethyl) aminoethanol was distilled off under reduced pressure. The oilyresidue was twice extracted with dilute hydrochloric acid. The acid extract was washed twicewith ether and a sodium carbonate solution until a precipitate formed. The precipitate was hi tered out, extracted with ether and the extract added to the Iiltrate,- the combination being dried ether distilled oil at atmospheric pressure. The oily remdue was di-N(ethyl,p-4-morpholylethyl) aminoethyi symmetrical diphenylsuccinate.

1. A chemical compound selected from the group consisting of the esters of a. carbocylic-substituted aliphatic; carboxylic acid andan N(alkyi,-

and the over sodium sulfate, filtered, and-the residual 1 A 2, 3.A chemical compound selected from the group consisting of the esters of a diaryl-suhstie tuted aliphatic 'carboxylic acid and an N(ethyl.-

beta-lmorpholylethyll aminoethanoi and the water-soluble salts and quaternary salts or the esters. i

4. A chemical compound selected from the gmiimconsisting oi N(ethyl.beta-4-morpholylethyl) aminoethyi diphenyla'cetate, its water-soiuble salts and quaternary salts.

5. A chemical compound from the group consisting of N(ethyl,beta-i-n i om'pholylethyliaminoethyl benzilate, its wateraolubl'e salts and quaternary salts.

6. A chemical compound selected from the group consisting or N(ethyl.beta-4-morphoiyiethyl) aminoethyl alpha,a lpha,-ditolylpropionate,

its water-soluble salts and quaternary salts,

ELMORE HA'I'HAWAY NORTBIY; 

